Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia

Abstract

The prognostic significance of FLT3 mutations in acute promyelocytic leukemia (APL) is not firmly established and is of particular interest given the opportunities for targeted therapies using FLT3 inhibitors. We studied 203 patients with PML-RARA-positive APL; 43% of the patients had an FLT3 mutation (65 internal tandem duplications [ITDs], 19 D835/I836, 4 ITD؉D835/I836). Both mutations were associated with higher white blood cell (WBC) count at presentation; 75% of the patients with WBC counts of 10 ؋ 10 9 /L or greater had mutant FLT3. FLT3/ITDs were correlated with M3v subtype (P < .001), bcr3 PML breakpoint (P < .001), and expression of reciprocal RARA-PML transcripts (P ‫؍‬ .01). Microarray analysis revealed differences in expression profiles among patients with FLT3/ITD, D835/I836, and wild-type FLT3. Patients with mutant FLT3 had a higher rate of induction death (19% vs 9%; P ‫؍‬ .04, but no significant difference in relapse risk (28% vs 23%; P ‫؍‬ .5) or overall survival (59% vs 67%; P ‫؍‬ .2) at 5 years. In in vitro differentiation assays using primary APL blasts (n ‫؍‬ 6), the FLT3 inhibitor CEP-701 had a greater effect on cell survival/proliferation in FLT3/ITD ؉ cells, but this inhibition was reduced in the presence of ATRA. IntroductionMost cases of acute promyelocytic leukemia (APL) are characterized by t(15;17)(q22;q21) leading to formation of the promyelocytic leukemia-retinoic acid receptor ␣ (PML-RARA) fusion protein. 1 PML-RARA plays a critical role in determining disease phenotype, mediating the characteristic differentiation block through the repression of genes implicated in myelopoiesis, which is overcome by pharmacologic levels of retinoic acid. 1 However, evidence derived largely from transgenic mouse models has suggested that PML-RARA is insufficient for leukemogenesis, 2,3 although the precise nature of the cooperating events implicated in generating the full disease phenotype remains uncertain. A number of potential candidates have been proposed to play a role in this process. These include the reciprocal fusion gene product RARA-PML, which is expressed in approximately 75% of patients [4][5][6] and has been postulated to contribute to leukemogenesis by promoting genomic instability, thereby predisposing to the acquisition of additional oncogenic lesions. 7 There has also been considerable interest in the potential role of activating mutations of genes encoding receptor tyrosine kinases (RTKs), which commonly accompany acute myelocytic leukemia (AML)-associated translocations including t(15;17), giving rise to the proposition that they could provide a common class of cooperating mutation in the development of the disease. 8 Fms-like tyrosine kinase 3 (FLT3) is an RTK expressed on hematopoietic progenitors. Mutation of the FLT3 gene is common in AML. [9][10][11][12] Numerous mutations have been identified. The majority, present in approximately 25% of patients, are internal tandem duplications (ITDs) that lead to in-frame insertions within the juxtamembrane region of the receptor. Le...

Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA

“…We were further able to confirm the 0.5 threshold for the FLT3-ITD/wt ratio to be prognostically relevant specifically in the induction period within the first 30 days from the start of therapy. Consistent with our results, Chillon et al described an increasing FLT3-Impact of FLT3-ITD mutation load in acute promyelocytic leukemia haematologica | 2011; 96 (12) 1803 29 This was similar to the findings of Au et al who described a clearly adverse impact of the FLT3-ITD on the achievement of remission (P=0.06), but failed to demonstrate a significant impact of the FLT3-ITD mutation status on disease-free survival in APL patients. 31 Noguera et al reported a non-significant trend for worse disease-free survival or relapse risk in haematologica | 2011; 96(12) …”

“…We, therefore, investigated the clinical impact of FLT3-ITD and FLT3-TKD, and other parameters in 147 patients with APL at diagnosis. First, we were able to confirm the high frequency of FLT3 mutations in APL, 12,29 as 44.2% of patients had either an ITD or TKD or both (one case). The presence of FLT3-ITD was associated with specific characteristics, i.e.…”

“…higher WBC counts, lower platelet counts, a preponderance of the M3v subtype, and of the bcr3 PML-RARA fusion transcript (P<0.001 for all parameters) when compared to ITD-negative patients, confirming findings of other study groups. [29][30] FLT3-TKD mutated patients differed from FLT3-TKD negative cases by having lower platelet counts (P=0.006) and a higher frequency of ACA (P=0.080).…”

“…In contrast, Gale et al described a worse overall survival, of borderline statistical significance, in APL patients with FLT3-TKD (P=0.05). 29 The mean FLT3-ITD/wt ratio was significantly lower (P<0.001) in APL patients than in a cohort of 197 patients with FLT3-ITD-positive normal karyotype acute myeloid leukemia 25 which we had previously analyzed. It remains speculative whether this aspect could contribute to explain the weaker prognostic impact of the FLT3-ITD in Impact of FLT3-ITD mutation load in acute promyelocytic leukemia haematologica | 2011; 96(12) The frequency of ACA in our cohort (38.8%) was similar to that in previous studies.…”

Clinical outcome of de novo acute myeloid leukaemia patients with normal cytogenetics is affected by molecular genetic alterations: a concise review

“…We would like, however, to underscore the importance of performing molecular genetic studies in AML within clearly defined cytogenetic groups of patients, such as CN-AML, as the prognostic significance of molecular alterations often depends on cytogenetic status. This is exemplified by the adverse impact of FLT3-ITD on remission duration and overall survival in CN-AML patients (Table I) but not in patients with acute promyelocytic leukaemia with t(15;17)(q22;q21)/PML-RARA (Gale et al, 2005b).…”